Cancer vaccine clinical trials performed over the last few years have demonstrated that cancer patients can be immunized against specific tumor antigens. Studies performed by our group, targeting the HER-2/neu (HER2) antigen, have demonstrated that HER2 specific T-cell precursor frequencies can be significantly boosted and determinant spreading can be elicited with active immunization. Determinant spreading indicates that a cancer patient is developing a native immune response to multiple epitopes from a specific antigen as well as multiple antigens present in existing tumor. Thus, both the magnitude as well as the character of the immune response elicited with immunization may be important in predicting vaccine efficacy. Cancer, however, is not caused by a single genetic alteration but rather by multiple genetic alterations and the function of multiple aberrant proteins. A problem facing tumor immunologists today is how to vaccinate cancer patients against multiple antigens involved in the malignant transformation. DNA based immunization offers a technology that is easily adapted to the delivery of multiple antigens driving the malignant process. Immunization with plasmid DNA, however, has not resulted in the reproducible generation of systemic immunity in a variety of models of infectious disease antigens. We hypothesize it will be possible to improve the efficacy of in vivo transfection of antigen presenting cells (APC) with tumor antigen DNA by the use of local soluble cytokines such as GM-CSF. GM-CSF has utility and safety as a vaccine adjuvant. Local influx of skin Langerhans' cells (LC) induced by GM-CSF and application of plasmid DNA to the epidermis rather than muscle may improve the immunogenicity of plasmid DNA vaccines. The specific aims of this proposal are to: (1) determine the safety of HER2 ICD plasmid-based DNA vaccination in patients with advanced stage HER2 overexpressing breast and ovarian cancer, (2) determine the immunogenicity of HER2 ICD plasmid-based DNA vaccination in patients with advanced stage HER2 overexpressing breast and ovarian cancer, and, (3) determine if the dose of HER2 ICD plasmid-based DNA vaccination effects the development of an immune response. The long-term goal will be to use this study as a platform to develop multi-antigen plasmid based vaccines for the prevention of common solid tumors.